CN113307781B - Synthesis method of 1,2, 3-thiadiazole derivative - Google Patents

Synthesis method of 1,2, 3-thiadiazole derivative Download PDF

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CN113307781B
CN113307781B CN202110339482.3A CN202110339482A CN113307781B CN 113307781 B CN113307781 B CN 113307781B CN 202110339482 A CN202110339482 A CN 202110339482A CN 113307781 B CN113307781 B CN 113307781B
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thiadiazole
reaction
nmr
acetophenone
cdcl
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CN113307781A (en
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阿布力米提·阿布都卡德尔
陆雨函
买尔哈巴·买买提
孙亚栋
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Xinjiang University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

The invention belongs to the technical field of compound preparation, and discloses a synthesis method of a1, 2, 3-thiadiazole derivative, wherein the synthesis method of the 1,2, 3-thiadiazole derivative comprises the following steps: n-p-toluenesulfonyl hydrazone acetophenone derivatives are used as raw materials, and are subjected to [4+1] cyclization reaction with ammonium thiocyanate under the metal-free condition to generate the 1,2, 3-thiadiazole derivatives. The invention relates to a method for preparing 1,2, 3-thiadiazole derivatives through iodine simple substance mediated metal-free. Under the condition of no metal, N-p-toluenesulfonyl hydrazone acetophenone is used as a raw material, low-cost iodine simple substance participates in mediation, potassium persulfate is used as an oxidant, absolute ethyl alcohol is used as a solvent, and [4+1] cyclization reaction is carried out at room temperature to construct the 1,2, 3-thiadiazole derivative. The invention is green and environment-friendly, does not need inert gas protection and heating, has wide substrate application range, good functional group compatibility, easily available raw materials and simple and convenient operation.

Description

Synthesis method of 1,2, 3-thiadiazole derivative
Technical Field
The invention belongs to the technical field of compound preparation, and particularly relates to a synthesis method of a1, 2, 3-thiadiazole derivative.
Background
At present, the 1,2, 3-thiadiazole derivative is an important heterocyclic compound and has wide application in the fields of functional materials, medicines and pesticides .((a)Amirhamzeh,M.Vosoughi,A.Shafiee andM.Amini,Med.Chem.Res.,2013,22,1212.(b)I.Cikotiene,E.Kazlauskas,J.Matuliene,V.Michailoviene,J.Torresan,J.Jachno and D.Matulis,Bioorg.Med.Chem.Lett.,2009,19,1089;(c)Q.Zheng,N.Mi,Z.Fan,X.Zuo,H.Zhang,H.Wang and Z.Yang,J.Agric.Food Chem.,2010,58,7846;(d)S.M.S.Atta,D.S.Farrag,A.M.K.Sweed andA.H.Abdel-Rahman,Eur.J.Med.Chem.,2010,45,4920;(e)M.Wu,Q.Sun,C.Yang,D.Chen,J.Ding,Y.Chen,L.Lin and Y.Xie,Bioorg.Med.Chem.Lett.,2007,17,869;(f)H.Dai,S.Ge,G.Li,J.Chen,Y.Shi,L.Ye andY.Ling,Bioorg.Med.Chem.Lett.,2016,26,4504;(g)P.Zhan,X.Liu,Y.Cao,Y.Wang,C.Pannecouque and E.De Clercq,Bioorg.Med.Chem.Lett.,2008,18,5368;(h)Q.Du,W.Zhu,Z.Zhao,X.Qian and Y.Xu,J.Agric.Food Chem.,2012,60,346;(i)Y.Xu,Z.Zhao,X.Qian,Z.Qian,W.Tian and J.Zhong,J.Agric.Food Chem.,2006,54,8793;(j)Z.-H.Wang,Y.-Z.Guo,J.Zhang,L.Ma,H.-B.Song and Z.-J.Fan,J.Agric.Food Chem.,2010,58,2715;(k)X.Zuo,N.Mi,Z.Fan,Q.Zheng,H.Zhang,H.Wang and Z.Yang,J.Agric.Food Chem.,2010,58,2755.).
At present, the reported synthesis method of the 1,2, 3-thiadiazole derivative mainly comprises two approaches, namely (1) under the electrocatalytic action, N-p-toluenesulfonyl hydrazone acetophenone and sulfur simple substance are used for constructing 1,2, 3-thiadiazole and the derivative thereof (S.—K.Mo, Q.—H.teng, Y.—M.Pan and H.—T.adv.Synth.catalyst.. 2019,361,1756); (2) Under the combined action of iodine, lewis acid and cuprous chloride, the N-p-toluenesulfonyl hydrazone acetophenone and potassium thiocyanate are used for constructing 1,2, 3-thiadiazole and derivatives thereof under the heating condition (C.Wang, X.Geng, P.Zhao, Y.Zhou, Y. -D.Wu, Y. -F.Cui anada. -X.Wu, chem.Commun.,2019,55,8134.). The method has the defects that high temperature is required, lewis acid is used as an additive, a solvent is not green, and the substrate range is not wide.
Through the above analysis, the problems and defects existing in the prior art are as follows: the reported synthesis method of the 1,2, 3-thiadiazole derivative has the defects of high temperature requirement, lewis acid as an additive, non-green solvent and non-wide substrate range.
The difficulty of solving the problems and the defects is as follows: firstly, carrying out a reaction under the condition of normal temperature, which has a certain test on the dissolution degree of the reaction substrate in the temperature; in addition, the target product with better yield can be obtained without adding extra acid and alkali; finally, there is a need to find a solvent which is more environmentally friendly than that used in the previous reactions and which ensures that the reaction proceeds as desired in the solvent and gives higher yields.
The meaning of solving the problems and the defects is as follows: the method has the advantages that no extra transition metal and acid-base compound are needed to be added, under the condition of no metal, N-p-toluenesulfonyl hydrazone acetophenone is used as a raw material, low-cost iodine simple substance participates in mediation, potassium persulfate is used as an oxidant, absolute ethyl alcohol is used as a solvent, and 1,2, 3-thiadiazole derivatives are efficiently synthesized at room temperature.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a synthesis method of a1, 2, 3-thiadiazole derivative.
The invention is realized in such a way that a1, 2, 3-thiadiazole derivative has the structural formula:
The substituent R is hydrogen or R is halogen F, halogen Cl, halogen Br, halogen I or one or two of alkyl, alkoxy, phenyl, nitro, thienyl, furyl, naphthyl, (E) -styryl, fluoroalkyl and fluoroalkoxy; the number of the substituents is 1-2.
Another object of the present invention is to provide a method for synthesizing a1, 2, 3-thiadiazole derivative of a1, 2, 3-thiadiazole derivative according to claim 1, wherein the method for synthesizing a1, 2, 3-thiadiazole derivative comprises: n-p-toluenesulfonyl hydrazone acetophenone derivative 2 is used as a raw material, and is subjected to [4+1] cyclization reaction with ammonium thiocyanate under a metal-free condition to generate 1,2, 3-thiadiazole derivative 1.
Further, the synthesis method of the 1,2, 3-thiadiazole derivative comprises the following steps:
Step one, in a reaction test tube, adding 0.25mmol of N-p-toluenesulfonyl hydrazone acetophenone or N-p-toluenesulfonyl hydrazone acetophenone derivative 2 and 0.25mmol (19 mg) of ammonium thiocyanate 3;
Step two, adding an oxidant into the test tube: 0.25mmol (68 mg) of potassium persulfate;
Setting the reaction temperature and the reaction time, adding 3ml of absolute ethyl alcohol solvent into a test tube, and then placing the test tube into an oil bath for reaction;
Step four, separating products after the reaction is finished: firstly, adding sodium thiosulfate into the mixed solution to remove redundant iodine in the mixed solution, adding 30ml of water, then adding 10ml of ethyl acetate into the water for three times to extract organic matters, adding anhydrous magnesium sulfate into the obtained extract to remove redundant water in the solution, evaporating the solution by a rotary evaporator, separating the product by a column chromatography method, wherein the proportion of the developing agent is as follows: ethyl acetate: petroleum ether (8:1) to finally obtain the 1,2, 3-thiadiazole derivative 1.
Further, the molar ratio of the N-p-toluenesulfonyl hydrazone acetophenone or the N-p-toluenesulfonyl hydrazone acetophenone derivative 2 to the ammonium thiocyanate 3 is 1:1-1:3; the molar ratio is preferably 1:1.
Further, the additive is one of potassium iodide, ammonium iodide, cuprous iodide, tetrabutylammonium iodide, diacetyl iodobenzene and iodine; the additive is preferably iodine.
Further, the oxidant is one of potassium persulfate, ammonium persulfate and tert-butyl hydroperoxide; the oxidizing agent is preferably potassium persulfate.
Further, the solvent is one of absolute ethyl alcohol, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide acetonitrile; the solvent is preferably absolute ethanol.
Further, the reaction time is 1 to 12 hours; the reaction time is preferably 10 to 12 hours.
Further, the reaction temperature is from room temperature to 100 ℃; the reaction temperature is preferably room temperature.
Further, the reaction general formula of the synthesis method of the 1,2, 3-thiadiazole derivative is as follows:
The substituent R is hydrogen or R is halogen F, halogen Cl, halogen Br, halogen I or one or more than two of alkyl, alkoxy, phenyl, nitro, thienyl, furyl, naphthyl, (E) -styryl, fluoroalkyl and fluoroalkoxy; the number of the substituents is 1-2.
By combining all the technical schemes, the invention has the advantages and positive effects that: the invention provides a method for preparing a 1,2, 3-thiadiazole derivative through iodine simple substance mediated metal-free preparation. Under the condition of no metal, the 1,2, 3-thiadiazole derivative is efficiently synthesized at room temperature by taking N-p-toluenesulfonyl hydrazone acetophenone as a raw material, taking low-cost iodine simple substance as a mediator, taking potassium persulfate as an oxidant and taking absolute ethyl alcohol as a solvent. Compared with the reported preparation method of the 1,2, 3-thiadiazole derivative, the synthesis method is green and environment-friendly, does not need inert gas protection and heating, and has the advantages of wide substrate application range, good functional group compatibility, easily available raw materials and simple and convenient operation.
Under the condition of no metal, the invention takes N-p-toluenesulfonyl hydrazone acetophenone and ammonium thiocyanate as raw materials, takes low-cost iodine simple substance as an additive, and synthesizes the 1,2, 3-thiadiazole efficiently. The reaction is simple and convenient to operate, environment-friendly and carried out at room temperature, and a metal catalyst is not needed. The invention is completed under the fund of national natural foundation (22061040) and Xinjiang Uygur autonomous region natural science foundation (2020D 01C 024).
The invention is used for organic reaction under the condition of no metal, and uses environment-friendly absolute ethyl alcohol as a solvent. The reaction is carried out at normal temperature and normal pressure, no extra alkali or inert gas is needed for protection, and the operation and the post-treatment are simple and convenient. The low-cost iodine simple substance is used as an additive, so that the use of transition metal is avoided. The raw materials are simple and easy to obtain.
The invention relates to a method for preparing 1,2, 3-thiadiazole derivatives through iodine simple substance mediated metal-free. Under the condition of no metal, N-p-toluenesulfonyl hydrazone acetophenone is used as a raw material, low-cost iodine simple substance participates in mediation, potassium persulfate is used as an oxidant, absolute ethyl alcohol is used as a solvent, and [4+1] cyclization reaction is carried out at room temperature to construct the 1,2, 3-thiadiazole derivative. The invention is green and environment-friendly, does not need inert gas protection and heating, has wide substrate application range, good functional group compatibility, easily available raw materials and simple and convenient operation.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the embodiments of the present application will be briefly described below, and it is obvious that the drawings described below are only some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a flow chart of a synthetic method of a1, 2, 3-thiadiazole derivative provided by the embodiment of the invention.
FIG. 2 is 1 H NMR of 4-phenyl-1, 2, 3-thiadiazole (deuterated chloroform CDCl 3 as solvent) provided in the examples of the present invention.
FIG. 3 is 13 C NMR of 4-phenyl-1, 2, 3-thiadiazole provided in the example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 4 is 1 H NMR of 4- (4-methyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 5 is 13 C NMR of 4- (4-methyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 6 is 1 H NMR of 4- (2-methyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 7 is 13 C NMR of 4- (2-methyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 8 is 1 H NMR of 4- (3, 4-dimethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 9 is 13 C NMR of 4- (3, 4-dimethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 10 is 1 H NMR of 4- (2, 4-dimethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 11 is 13 C NMR of 4- (2, 4-dimethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 12 is 1 H NMR of 4- (4-tert-butyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 13 is 13 C NMR of 4- (4-tert-butyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 14 is 1 H NMR of 4- (4-isopropyl-phenyl) -1,2, 3-thiadiazole provided in the present example (deuterated chloroform CDCl 3 as solvent).
FIG. 15 is 13 C NMR of 4- (4-isopropyl-phenyl) -1,2, 3-thiadiazole provided in the present example (deuterated chloroform CDCl 13 as solvent).
FIG. 16 is 1 H NMR of 4- (2-methoxy-phenyl) -1,2, 3-thiadiazole provided in the present example (deuterated chloroform CDCl 3 as solvent).
FIG. 17 is 13 C NMR of 4- (2-methoxy-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 18 is 1 H NMR of 4- (2-hydroxy-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 19 is 13 C NMR of 4- (2-hydroxy-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 20 is 1 H NMR of 4- (4-N, N-dimethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 21 is 13 C NMR of 4- (4-N, N-dimethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 22 is 1 H NMR of 4- ([ 1,1' -biphenyl ] -4-yl) -1,2, 3-thiadiazole provided in the example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 23 is 13 C NMR of 4- ([ 1,1' -biphenyl ] -4-yl) -1,2, 3-thiadiazole provided in the example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 24 is 1 H NMR of 4- (benzo [ d ] [1,3] dioxa-5-yl) -1,2, 3-thiadiazole provided by an example of the invention (deuterated chloroform CDCl 3 as solvent).
FIG. 25 is 13 C NMR of 4- (benzo [ d ] [1,3] dioxa-5-yl) -1,2, 3-thiadiazole provided by an example of the invention (deuterated chloroform CDCl 13 as solvent).
FIG. 26 is 1 H NMR of 4- (4-trifluoromethyl-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 27 is 13 C NMR of 4- (4-trifluoromethyl-phenyl) -1,2, 3-thiadiazole provided in an example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 28 is 1 H NMR of 4- (4-trifluoromethoxy-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 29 is 13 C NMR of 4- (4-trifluoromethoxy-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 30 is 1 H NMR of 4- (4-cyano-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 31 is 13 C NMR of 4- (4-cyano-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 32 is 1 H NMR of 4- (4-chloro-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 33 is 13 C NMR of 4- (4-chloro-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 34 is 1 H NMR of 4- (3, 4-dichloro-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 35 is 13 C NMR of 4- (3, 4-dichloro-phenyl) -1,2, 3-thiadiazole provided in the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 36 is 1 H NMR of 4- (4-fluoro-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 37 is 13 C NMR of 4- (4-fluoro-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 38 is 1 H NMR of 4- (3-bromo-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 39 is 13 C NMR of 4- (3-bromo-phenyl) -1,2, 3-thiadiazole provided in the example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 40 is 1 H NMR of 4- (4-bromo-phenyl) -1,2, 3-thiadiazole provided in the present example (deuterated chloroform CDCl 3 as solvent).
FIG. 41 is 13 C NMR of 4- (4-bromo-phenyl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 42 is 1 H NMR of 4- (4-iodo-phenyl) -1,2, 3-thiadiazole provided in example of the invention (deuterated chloroform CDCl 3 as solvent).
FIG. 43 is 13 C NMR of 4- (4-iodo-phenyl) -1,2, 3-thiadiazole provided in example of the invention (deuterated chloroform CDCl 13 as solvent).
FIG. 44 is 1 H NMR of 4- (thiophen-2-yl) -1,2, 3-thiadiazole provided in example of the invention (deuterated chloroform CDCl 3 as solvent).
FIG. 45 is 13 C NMR of 4- (thiophen-2-yl) -1,2, 3-thiadiazole provided in example of the invention (deuterated chloroform CDCl 13 as solvent).
FIG. 46 is 1 H NMR of 4- (furan-2-yl) -1,2, 3-thiadiazole provided in example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 47 is 13 C NMR of 4- (furan-2-yl) -1,2, 3-thiadiazole provided in an example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 48 is 1 H NMR of 4- (naphthalen-1-yl) -1,2, 3-thiadiazole provided in an example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 49 is 13 C NMR of 4- (naphthalen-1-yl) -1,2, 3-thiadiazole provided in an example of the invention (deuterated chloroform CDCl 13 as solvent).
FIG. 50 is 1 H NMR of (E) -4-styryl-1, 2, 3-thiadiazole (deuterated chloroform CDCl 3 as solvent) provided in an example of the present invention.
FIG. 51 is 13 C NMR of (E) -4-styryl-1, 2, 3-thiadiazole (deuterated chloroform CDCl 13 as solvent) provided in an example of the present invention.
FIG. 52 is 1 H NMR of 4- (4- (phenylethynyl) phenyl) -1,2, 3-thiadiazole provided in an example of the present invention (deuterated chloroform CDCl 3 as solvent).
FIG. 53 is 13 C NMR of 4- (4- (phenylethynyl) phenyl) -1,2, 3-thiadiazole provided in an example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 54 is 1 H NMR of 4- ([ 1,1' -biphenyl ]) -4-yl-1, 2, 3-thiadiazole (deuterated chloroform CDCl 3 as solvent) provided in an example of the present invention.
FIG. 55 is 13 C NMR of 4- ([ 1,1' -biphenyl ]) -4-yl-1, 2, 3-thiadiazole provided in the example of the present invention (deuterated chloroform CDCl 13 as solvent).
FIG. 56 is a synthetic route diagram of 1,2, 3-thiadiazole derivatives provided in examples of the present invention.
FIG. 57 is a schematic diagram of a synthetic route for 1,2, 3-thiadiazole derivatives provided in an embodiment of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The present invention provides a method for synthesizing a1, 2, 3-thiadiazole derivative, which is described in detail below with reference to the accompanying drawings.
The structural formula of the 1,2, 3-thiadiazole derivative provided by the embodiment of the invention is as follows:
The substituent R is hydrogen or R is halogen F, halogen Cl, halogen Br, halogen I or one or more than two of alkyl, alkoxy, phenyl, nitro, thienyl, furyl, naphthyl, (E) -styryl, fluoroalkyl and fluoroalkoxy; the number of the substituents is 1-2.
The synthesis method of the 1,2, 3-thiadiazole derivative provided by the embodiment of the invention comprises the following steps: n-p-toluenesulfonyl hydrazone acetophenone derivative 2 is used as a raw material, and is subjected to [4+1] cyclization reaction with ammonium thiocyanate under a metal-free condition to generate 1,2, 3-thiadiazole derivative 1. Based on the prior synthesis method, we propose to synthesize a1, 2, 3-thiadiazole compound efficiently under the conditions that no acid or alkali is additionally added in the reaction, the reaction is not heated, and the solvent is relatively green and environment-friendly.
As shown in fig. 1, the synthesis method of the 1,2, 3-thiadiazole derivative provided by the embodiment of the invention comprises the following steps:
s101, firstly adding 0.25mmol of N-p-toluenesulfonyl hydrazone acetophenone or N-p-toluenesulfonyl hydrazone acetophenone derivative 2 and 0.25mmol (19 mg) of ammonium thiocyanate 3 into a reaction test tube;
s102, adding an oxidant into the test tube: 0.25mmol (68 mg) of potassium persulfate;
S103, setting the reaction temperature and the reaction time, adding 3ml of absolute ethyl alcohol solvent into a test tube, and then placing the test tube into an oil bath for reaction;
S104, stopping the reaction when the reaction time reaches 12 hours, and then separating products: firstly, adding sodium thiosulfate into the mixed solution to remove redundant iodine in the mixed solution, adding 30ml of water, then adding 10ml of ethyl acetate into the water for three times to extract organic matters, adding anhydrous magnesium sulfate into the obtained extract to remove redundant water in the solution, evaporating the solution by a rotary evaporator, separating the product by a column chromatography method, wherein the proportion of the developing agent is as follows: ethyl acetate: petroleum ether (8:1) to finally obtain the 1,2, 3-thiadiazole derivative 1.
The molar ratio of the N-p-toluenesulfonyl hydrazone acetophenone or the N-p-toluenesulfonyl hydrazone acetophenone derivative 2 to the ammonium thiocyanate 3 provided by the embodiment of the invention is 1:1-1:3; the molar ratio is preferably 1:1.
The additive provided by the embodiment of the invention is one of potassium iodide, ammonium iodide, cuprous iodide, tetrabutylammonium iodide, diacetyl iodobenzene and iodine; the additive is preferably iodine.
The oxidant provided by the embodiment of the invention is one of potassium persulfate, ammonium persulfate and tert-butyl hydroperoxide; the oxidizing agent is preferably potassium persulfate.
The solvent provided by the embodiment of the invention is one of absolute ethyl alcohol, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide acetonitrile; the solvent is preferably absolute ethanol.
The reaction time provided by the embodiment of the invention is 1-12 hours; the reaction time is preferably 10 to 12 hours.
The reaction temperature provided by the embodiment of the invention is between room temperature and 100 ℃; the reaction temperature is preferably room temperature.
The reaction general formula of the synthesis method of the 1,2, 3-thiadiazole derivative provided by the embodiment of the invention is as follows:
The substituent R is hydrogen or R is halogen F, halogen Cl, halogen Br, halogen I or one or more than two of alkyl, alkoxy, phenyl, nitro, thienyl, furyl, naphthyl, (E) -styryl, fluoroalkyl and fluoroalkoxy; the number of the substituents is 1-2.
The technical scheme of the present invention is further described below with reference to examples.
Example 1
N-p-toluenesulfonyl hydrazone acetophenone 2a (72.0 mg,0.25 mmol), ammonium thiocyanate 3 (19 mg,0.25 mmol), iodine (63.5 mg,0.25 mmol), potassium persulfate (67.6 mg,0.25 mmol) and 2mL absolute ethyl alcohol are sequentially added into a 10mL quartz reaction tube with a stirrer under the normal temperature and air atmosphere, and the mixture is stirred and reacted for 12 hours; after the reaction, 1-2 drops of saturated sodium thiosulfate solution are firstly dripped into the mixed reactant, then ethyl acetate is used for extraction (3X 10 mL), the organic layers are combined, anhydrous sodium sulfate is used for drying, volatile components are removed under reduced pressure and then silica gel column chromatography is used for separation (eluent is petroleum ether (60-90 ℃ C. Fraction)/ethyl acetate, v/v=8:1) to obtain a white solid target product 1a (35.3 mg, yield 87%); the target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Example 2
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference from the example 1 is that potassium iodide is added in the reaction to replace iodine simple substance; stopping the reaction, and carrying out the same post treatment as the above to obtain a target product 1a (25.5 mg, yield 63%); it was revealed that when potassium iodide was an iodide salt, the target product could not be obtained in an optimal yield.
Example 3
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference is that ammonium iodide is added in the reaction to replace the iodine simple substance; the reaction was stopped and the desired product 1a (32.8 mg, yield 81%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield when the ammonium iodide was iodinated.
Example 4
The reaction steps and the operation conditions of the invention are the same as those of the embodiment 1, and the difference is that cuprous iodide is added to replace iodine simple substance in the reaction; the reaction was stopped and the desired product 1a (29.2 mg, yield 72%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield when the cuprous iodide was iodinated.
Example 5
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference from the example 1 is that tetrabutylammonium iodide is added in the reaction to replace the iodine simple substance; the reaction was stopped and the same post-treatment as above was performed to obtain the target product 1a (31.6 mg, yield 78%), indicating that the target product was obtained in the optimum yield when tetrabutylammonium iodide was iodinated.
Example 6
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference from the example 1 is that diacetyl iodobenzene is added in the reaction to replace the iodine simple substance; the reaction was stopped and the same post-treatment as above was performed to obtain the target product 1a (28.4 mg, yield 70%), indicating that the target product was obtained in the optimum yield when diacetyl iodobenzene was the iodonium salt.
Example 7
The reaction steps and the operation conditions of the present invention are the same as those of example 1, except that the oxidizer potassium persulfate is replaced with ammonium persulfate; the reaction was stopped and the desired product 1a (29.9 mg, yield 74%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield when ammonium persulfate was used as the oxidizing agent.
Example 8
The steps and operating conditions of the invention are the same as those of example 1, except that the oxidant potassium persulfate is replaced by hydrogen peroxide; the reaction was stopped and the desired product 1a (21.5 mg, 53% yield) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield when hydrogen peroxide was used as the oxidizing agent.
Example 9
The reaction steps and operating conditions of the present invention were the same as in example 1, except that the oxidant potassium persulfate was replaced with t-butyl hydroperoxide; the reaction was stopped and the desired product 1a (23.1 mg, yield 57%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield when t-butyl hydroperoxide was used as the oxidizing agent.
Example 10
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference is that N, N-dimethylformamide is added in the reaction to replace absolute ethyl alcohol; the reaction was stopped and the desired product 1a (30.8 mg, yield 76%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield by using dimethyl sulfoxide as a solvent.
Example 11
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference is that dimethyl sulfoxide is added to replace absolute ethyl alcohol in the reaction; the reaction was stopped and the desired product 1a (31.6 mg, yield 78%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield by using dimethyl sulfoxide as a solvent.
Example 12
The reaction steps and the operation conditions of the invention are the same as those of the example 1, and the difference from the example 1 is that N, N-dimethylacetamide is added in the reaction to replace absolute ethyl alcohol; the reaction was stopped and the desired product 1a (25.1 mg, yield 62%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield by using N, N-dimethylacetamide as a solvent.
Example 13
The reaction steps and the operation of the invention are the same as those of the example 1, and the difference is that acetonitrile is added to replace absolute ethyl alcohol in the reaction; the reaction was stopped and the desired product 1a (19.0 mg, yield 47%) was obtained by the same post-treatment as above, indicating that the desired product could not be obtained in the optimum yield by using acetonitrile as a solvent.
Example 14
The reaction steps and operations of the present invention are the same as those of example 1, except that potassium persulfate is not added in the reaction; the reaction was stopped and the target product 1a (14.6 mg, yield 36%) was obtained by the same post-treatment as above, indicating that potassium persulfate plays an important role in the experiment and the reaction was suppressed without adding potassium persulfate.
Example 15
The reaction steps and operations of the invention are the same as those of example 1, except that ammonium thiocyanate 3 is not added in the reaction; the reaction was stopped and the target product 1a was not obtained by the same post-treatment as above, indicating that the sulfur atom in potassium persulfate did not participate in the reaction as a sulfur source instead of ammonium thiocyanate.
Example 16
The reaction steps and operations of the present invention were the same as in example 1, except that the reaction time was prolonged to 16 hours; the reaction was stopped and the desired product 1a (32.4 mg, yield 80%) was obtained by the same post-treatment as above, indicating that the product yield could not be improved by extending the reaction time.
Example 17
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-methyl N-p-toluenesulfonyl hydrazone acetophenone 2b (44 mg,0.25 mmol); the reaction was stopped, and a white solid target product 1b (34.8 mg, yield 85%) was obtained by post-treatment, and the target product was confirmed by nuclear magnetic resonance spectroscopy.
Example 18
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was o-methyl N-p-toluenesulfonyl hydrazone acetophenone 2c (44 mg,0.25 mmol); the reaction was stopped, and after working up, a yellow liquid target product 1c (29.5 mg, yield 72%) was obtained, which was confirmed by nuclear magnetic resonance spectroscopy.
Example 19
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was 3, 4-dimethyl N-p-toluenesulfonyl hydrazone acetophenone 2d (47.5 mg,0.25 mmol); the reaction was stopped and the desired product 1d (34.2 mg, 72% yield) was obtained as a brown oil by work-up and confirmed by nuclear magnetic resonance spectrometry and high resolution mass spectrometry.
Example 20
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was 2, 4-dimethyl N-p-toluenesulfonyl hydrazone acetophenone 2e (47.5 mg,0.25 mmol); the reaction was stopped and the desired product 1e (35.6 mg, 75% yield) was obtained as a yellow oil by work-up and confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Example 21
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-tert-butyl N-p-toluenesulfonyl hydrazone acetophenone 2f (54.5 mg,0.25 mmol); the reaction was stopped, and a white solid target product 1f (39.7 mg, yield 73%) was obtained by post-treatment, and the target product was confirmed by nuclear magnetic resonance spectroscopy.
Example 22
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was isopropyl N-p-toluenesulfonyl hydrazone acetophenone 2g (51.0 mg,0.25 mmol); the reaction was stopped, and 1g (40.0 mg, yield 78%) of a white solid target product was obtained by post-treatment, and the target product was confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Example 23
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was o-methoxy N-p-toluenesulfonyl hydrazone acetophenone 2h (48.0 mg,0.25 mmol); the reaction was stopped, and the target product was obtained as a yellow liquid by post-treatment for 1h (41.1 mg, yield 85%) and confirmed by nuclear magnetic resonance spectroscopy.
Example 24
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was o-hydroxy N-p-toluenesulfonyl hydrazone acetophenone 2i (44.5 mg,0.25 mmol); the reaction was stopped, and the target product 1i (28.6 mg, yield 69%) was obtained as a white solid after working up, and was confirmed by nuclear magnetic resonance spectroscopy.
Example 25
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was N, N-dimethyl N-p-toluenesulfonyl hydrazone acetophenone 2j (51.25 mg,0.25 mmol); the reaction was stopped and post-treatment gave the target product 1j (42.1 mg, 82% yield) as a brown solid, which was confirmed by nmr spectrometry and high resolution mass spectrometry.
Example 26
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was 2l (59.5 mg,0.25 mmol) of benzo [ d ] [1,3] dioxa-5-yl N-p-toluenesulfonyl hydrazone acetophenone; the reaction was stopped, and 1l (40.1 mg, yield 78%) of a yellow solid target product was obtained by post-treatment, and the target product was confirmed by nuclear magnetic resonance spectroscopy.
Example 27
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-trifluoromethyl N-p-toluenesulfonyl hydrazone acetophenone 2m (57.5 mg,0.25 mmol); the reaction was stopped, and the target product 1m (39.1 mg, yield 68%) was obtained as a white solid after working up, and confirmed by nuclear magnetic resonance spectroscopy.
Example 28
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-trifluoromethoxy N-p-toluenesulfonyl hydrazone acetophenone 2N (61.5 mg,0.25 mmol); the reaction was stopped and the target product 1n (48.0 mg, 78% yield) was obtained as a white solid by post-treatment, which was confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Example 29
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-cyano N-p-toluenesulfonyl hydrazone acetophenone 2o (46.8 mg,0.25 mmol); the reaction was stopped, and the target product 1o (37.4 mg, yield 80%) was obtained as a white solid after working up, and was confirmed by nuclear magnetic resonance spectroscopy.
Example 30
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-chloro N-p-toluenesulfonyl hydrazone acetophenone 2p (49.2 mg,0.25 mmol); the reaction was stopped, and after working up, the target product 1p (37.1 mg, 80% yield) was obtained as a white solid, which was confirmed by nuclear magnetic resonance spectroscopy.
Example 31
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was m-bromo N-p-toluenesulfonyl hydrazone acetophenone 2s (60.2 mg,0.25 mmol); the reaction was stopped, and the target product was obtained as a white solid by post-treatment for 1s (35.5 mg, yield 85%) and confirmed by nuclear magnetic resonance spectroscopy.
Example 32
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was p-bromo N-p-toluenesulfonyl hydrazone acetophenone 2t (60.2 mg,0.25 mmol); the reaction was stopped, and after working up, 1t (47.0 mg, 82% yield) of the target product was obtained as a white solid, which was confirmed by nuclear magnetic resonance spectroscopy.
Example 33
The procedure of the present invention was as in example 1, except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was thienyl N-p-toluenesulfonyl hydrazone 2v (42.1 mg,0.25 mmol); the reaction was stopped, and after workup, a brown solid target product 1v (29.4 mg, 70% yield) was obtained, which was confirmed by nuclear magnetic resonance spectroscopy.
Example 34
The procedure of the present invention was as in example 1 except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was furyl N-p-toluenesulfonyl hydrazone 2w (38.0 mg,0.25 mmol); the reaction was stopped, and after working up, a brown liquid target product 1w (22.4 mg, 60% yield) was obtained, which was confirmed by nuclear magnetic resonance spectroscopy.
Example 35
The procedure of the present invention was as in example 1, except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was naphthyl N-p-toluenesulfonyl hydrazone 2x (53.1 mg,0.25 mmol); the reaction was stopped and the target product 1x (41 mg, 77% yield) was obtained as a white solid after working up and confirmed by nmr spectroscopy.
Example 36
The procedure of the present invention was as in example 1, except that the N-p-toluenesulfonyl hydrazone acetophenone derivative added in the reaction was (E) -styryl N-p-toluenesulfonyl hydrazone 2y (78.6 mg,0.25 mmol); the reaction was stopped and post-treatment gave the target product 1x (30.6 mg, 65% yield) as a white solid, which was confirmed by nmr spectroscopy.
Example 37
In the invention, 4- (4-bromo-phenyl) thiadiazole 2t (91.8 mg,0.25 mmol), phenylacetylene (1.2 equiv), bis (triphenylphosphine) palladium chloride (5 mol%), triphenylphosphine (5 mol%) and cuprous iodide (10 mol%) are respectively added into a 10mL quartz reaction tube with a stirrer under the atmosphere of normal temperature and nitrogen: heating to 50 ℃ in tetrahydrofuran (1:1), and stirring for reaction for 12 hours; after the reaction was completed, extraction was performed with ethyl acetate (3×10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and volatile components were removed under reduced pressure, followed by column chromatography on silica gel (petroleum ether (60-90 ℃ C. Fraction)/ethyl acetate, v/v=5:1 as eluent) to give the desired product 4 as a white solid (46.0 mg, yield 70%); the target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Example 38
In the invention, 4- (4-bromo-phenyl) thiadiazole 2t (91.8 mg,0.25 mmol), phenylboronic acid (1.5 equiv), tetrakis (triphenylphosphine) palladium (10 mol%), triphenylphosphine (5 mol%) and potassium carbonate (2.5 equiv) are added to a 10mL quartz reaction tube with a stirrer under a nitrogen atmosphere at normal temperature: ethanol: heating to 80 ℃ in water (20:5:1), and stirring for reaction for 12 hours; after the reaction was completed, extraction was performed with ethyl acetate (3×10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and volatile components were removed under reduced pressure, followed by column chromatography on silica gel (petroleum ether (60-90 ℃ C. Fraction)/ethyl acetate, v/v=5:1 as eluent) to give the objective product 5 as a white solid (49.4 mg, yield 83%); the target product was confirmed by nuclear magnetic resonance spectroscopy.
Example 39
Typical compound characterization data
4-Phenyl-1,2,3-thiadiazole (1 a): 94% yield; 35.5mg; white solid; the melting point is 75-77 ℃; as shown in fig. 2: 1 H NMR (400 mhz, cdcl 3) delta 8.65 (s, 1H), 8.05 (d, j=6.8 hz, 2H), 7.54-7.43 (m, 3H); as shown in fig. 3: 13 C NMR (100 MHz, CDCl 3) delta 162.8,130.8,129.9,129.4,129.1,127.4.
4- (P-tolyl) -1,2,3-thiadiazole (1 b) yield 85%;34.8mg; white solid; melting point is 73-74 ℃; as shown in fig. 4: 1H NMR(400MHz,CDCl3 ) δ8.58 (s, 1H), 7.93 (d, j=8.0 hz, 2H), 7.30 (d, j= 8.0,2H), 2.41 (s, 1H); as shown in fig. 5: 13C NMR(100MHz,CDCl3 ) Delta 162.9,139.4,129.8,129.3,127.9,127.2,21.3.
4- (O-tolyl) -1,2.3-thiadiazole (1 c) in 72% yield; 29.5mg; a yellow liquid; as shown in fig. 6: 1H NMR(400MHz,CDCl3 ) Delta 8.56 (s, 1H), 7.64 (d, j=7.6 hz, 1H), 7.38-7.30 (m, 3H), 2.45 (s, 3H); as shown in fig. 7: 13C NMR(100MHz,CDCl3 ) Delta 162.5,136.7,132.9,131.1,130.4,130.3,129.3,126.2,20.9.
4- (3, 4-DIMETHYLPHENYL) -1,2,3-thiadiazole (1 d): yield 72%;34.2mg; brown oil; FIG. 8 shows ：1H NMR(400MHz,CDCl3)δ8.56(s,1H),7.83(s,1H),7.74(d,J＝7.6Hz,1H),7.24(d,J＝8.0Hz,1H),2.34(s,3H),2.32(s,3H); and FIG. 9 shows theoretical value [ M+H ] +: 191.0637, measured value 191.0635 of HRMS of ：13C NMR(100MHz,CDCl3)δ163.0,138.1,137.4,130.3,129.2,128.5,128.3,124.7,19.8,19.7.C10H10N2S.
4- (2, 4-DIMETHYLPHENYL) -1,2,3-thiadiazole (1 e) yield 75%;35.6mg; yellow oily; ：1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.56(d,J＝7.6Hz,1H),7.18(s,1H),7.14(d,J＝8.0Hz,1H),2.43(s,3H),2.40(s,3H); as shown in FIG. 10 and theoretical value [ M+H ] +: 191.0637 of HRMS of ：13C NMR(100MHz,CDCl3)δ162.56,139.2,136.4,132.5,131.8,130.2,127.5,126.9,21.1,20.9.C10H10N2S as shown in FIG. 11, measured value: 191.0635.
4- (4- (Tert-butyl) phenyl) -1,2,3-thiadiazole (1 f) yield 73%;39.7mg; white solid; the melting point is 70-71 ℃; as shown in fig. 12: 1H NMR(400MHz,CDCl3 ) δ8.60 (s, 1H), 7.97 (d, j=8.4 hz, 2H), 7.53 (d, j=8.4 hz, 2H), 1.37 (s, 9H); as shown in fig. 13: 13C NMR(100MHz,CDCl3 ) Delta 162.8,152.6,129.4,127.9,127.1,126.1,34.7,31.2.
4- (4-Isopropylphenyl) -1,2,3-thiadiazole (1 g): yield 78%;40mg; white solid; melting point is 67-67 ℃; FIG. 14 shows ：1H NMR(400MHz,CDCl3)δ8.59(s,1H),7.97(d,J＝8.4Hz,2H),7.36(d,J＝8.0Hz,2H),3.03-2.92(m,1H),1.30(d,J＝7.2Hz,6H); and FIG. 15 shows theoretical value [ M+H ] +: 191.0794 of HRMS of ：13C NMR(100MHz,CDCl3)δ162.9,150.4,129.3,128.3,127.3,127.2,33.9,23.8.C11H12N2S, measured value 191.0792.
4- (2-Methoxyphenyl) -1,2,3-thiadiazole (1 h): yield 85%;41.1mg; a yellow liquid; ：1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.51(d,J＝8.0Hz,1H),7.41(t,J＝8.8Hz,1H),7.13(t,J＝7.6Hz,1H),7.05(d,J＝8.4Hz,1H),3.95(s,3H); as shown in fig. 16 is shown in fig. 17: 13C NMR(100MHz,CDCl3 ) Delta 158.4,156.3,133.3,130.4,130.3,121.1,119.6,111.2,55.5.
2- (1, 2, 3-Thiadiazol-4-yl) phenol (1 i): yield 69%;28.6mg; white solid; melting point is 157-159 ℃; ：1H NMR(400MHz,CDCl3)δ10.55(s,1H),8.80(s,1H),7.64(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.13(d,J＝9.2Hz,1H),6.98(t,J＝3.6Hz,1H); as shown in fig. 18 is shown in fig. 19: 13CNMR(100MHz,CDCl3 ) Delta 162.2,155.9,131.3,130.1,127.4,120.1,118.2,114.5.
N, N-dimethyl-4- (1, 2, 3-thiadiazol-4-yl) aniline (1 j): 82% yield; 42.1mg; brown solid; the melting point is 115-117 ℃; as shown in fig. 20: 1H NMR(400MHz,CDCl3 ) Delta 8.41 (s, 1H), 7.92 (d, j=8.8 hz, 2H), 6.82 (d, j=8.8 hz, 2H), 3.03 (s, 6H); theoretical value [ M+H ] +: 206.0746 of ：13C NMR(100MHz,CDCl3)δ163.4,150.9,128.3,128.3,126.7,112.4,40.4.C10H11N3S of HRMS shown in FIG. 21, measured value: 206.0744.
4- ([ 1,1' -Biphenyl ] -4-yl) -1,2,3-thiadiazole (1 k): 86% yield; 46mg; white solid at 183-184 ℃; ：1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.14-8.12(m,2H),7.76-7.74(m,2H),7.68-7.65(m,2H),7.50-7.46(m,2H),7.42-7.37(m,1H); as shown in fig. 22 is shown in fig. 23: 13C NMR(100MHz,CDCl3 ) Delta 162.5,142.2,140.2,129.8,129.7,128.9,127.8,127.8,127.7,127.0.
4- (Benzod ] [1,3] dioxal-5-yl) -1,2,3-thiadiazole (1 l): 78% yield; 40.1mg; yellow solid; the melting point is 124-125 ℃; as shown in fig. 24: 1H NMR(400MHz,CDCl3 ) Delta 8.50 (s, 1H), 7.55-7.52 (m, 2H), 6.92 (d, j=8.4 hz, 1H), 6.04 (s, 2H); as shown in fig. 25: 13C NMR(100MHz,CDCl3 ) Delta 162.5,148.5,148.3,128.8,124.9,121.4,108.8,107.7,101.4.
4- (4- (Trifluoromethyl) phenyl) -1,2,3-thiadiazole (1 m) yield 68%;39.1mg; white solid; the melting point is 70-72 ℃; as shown in fig. 26: 1H NMR(400MHz,CDCl3 ) Delta 8.77 (s, 1H), 8.16 (d, j=8.4 hz, 2H), 7.76 (d, j=8.4 hz, 2H); as shown in fig. 27 ：13C NMR(100MHz,CDCl3)δ161.3,134.0,131.4,131.2(q,JC-F＝33Hz),127.6,126.1(q,JC-F＝3.7Hz),123.8(q,JC-F＝271Hz).
4- (4- (Trifluoromethoxy) phenyl) -1,2,3-thiadiazole (1 n): yield 78%;48.0mg; white solid; melting point is 65-67 ℃; as shown in fig. 28: 1H NMR(400MHz,CDCl3 ) Delta 8.67 (s, 1H), 8.06 (d, j=8.4 hz, 2H), 7.33 (d, j=8.8 hz, 2H); theoretical value [ M+H ] +: 247.0147 of ：13C NMR(100MHz,CDCl3)δ161.4,149.8,130.5,129.4,128.8,121.6,120.4(q,JC-F＝256.5Hz).C9H5F3N2OS of HRMS shown in FIG. 29, measured value: 247.0145.
4- (1, 2, 3-Thiadiazol-4-yl) benzonitrile (1 o): 80% yield; 37.4mg; white solid; melting point is 109-110 ℃; as shown in fig. 30: 1H NMR(400MHz,CDCl3 ) δ8.81 (s, 1H), 8.19 (d, j=8.0 hz, 2H), 7.81 (d, j=8.4 hz, 2H); as shown in fig. 31: 13C NMR(100MHz,CDCl3 ) Delta 160.8,134.8,132.9,132.0,127.9,118.3,112.9.
4- (4-Chlorophenyl) -1,2,3-thiadiazole (1 p) yield 80%;37.1mg; white solid; the melting point is 136-138 ℃; as shown in fig. 32: 1H NMR(400MHz,CDCl3 ) δ8.64 (s, 1H), 7.97 (d, j=8.4 hz, 2H), 7.47 (d, j=8.4 hz, 2H); as shown in fig. 33: 13C NMR(100MHz,CDCl3 ) Delta 161.7,135.4,130.2,129.4,129.2,128.6.
4- (3, 4-Dichlorophenyl) -1,2,3-thiadiazole (1 q): 53% yield; 28.9mg; white solid; melting point is 139-140 ℃; as shown in fig. 34: 1H NMR(400MHz,CDCl3 ) δ8.68 (s, 1H), 8.13 (s, 1H), 7.86 (d, j=8.4 hz, 1H), 7.55 (d.J =8.8 hz, 1H); as shown in fig. 35: 13C NMR(100MHz,CDCl3 ) Delta 160.3,133.4,133.3,131.1,130.9,130.5,129.0,126.4.
4- (4-Fluorophenyl) -1,2,3-thiadiazole (1 r): 77% yield; 32.6mg; white solid; the melting point is 97-97 ℃; as shown in fig. 36: 1H NMR(400MHz,CDCl3 ) Delta 8.61 (s, 1H), 8.04-8.00 (m, 2H), 7.21-7.16 (m, 2H); as shown in FIG. 37 ：13C NMR(100MHz,CDCl3)δ163.3(d,JC-F＝248.2),161.8,129.8,129.2(d,JC-F＝9.0Hz),127.0(d,JC-F＝4.0Hz),116.2(d,JC-F＝22.0Hz).
4- (3-Bromophenyl) -1,2,3-thiadiazole (1 s): yield 85%;35.5mg; white solid; the melting point is 152-153 ℃; ：1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.18(s,1H),7.95(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H); as shown in fig. 38 is shown in fig. 39: 13CNMR(100MHz,CDCl3 ) Delta 161.2,132.6,132.3,130.8,130.7,130.3,125.9,123.2.
4- (4-Bromophenyl) -1,2,3-thiadiazole (1 t): 82% yield; 47.0mg; white solid; the melting point is 153-154 ℃; as shown in fig. 40: 1H NMR(400MHz,CDCl3 ) δ8.66 (s, 1H), 7.92 (d, j=8.4 hz, 2H), 7.64 (d, j=8.4 hz, 2H); as shown in fig. 41: 13C NMR(100MHz,CDCl3 ) Delta 161.7,132.3,130.2,129.7,128.8,123.6.
4- (4-Iodophenyl) -1,2,3-thiadiazole (1 u): yield 56%;38.6mg; white solid; melting point is 165-166 ℃; as shown in fig. 42: 1H NMR(400MHz,CDCl3 ) δ8.66 (s, 1H), 7.85 (d, j=8.4 hz, 2H), 7.79 (d, j=8.4 hz, 2H); as shown in fig. 43: 13C NMR(100MHz,CDCl3 ) Delta 161.8,138.3,130.2,130.2,128.9,95.4.
4- (Thiophen-2-yl) -1,2,3-thiadiazole (1 v): yield 70%;29.4mg; brown solid; melting point is 71-72 ℃; ：1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.65(d,J＝3.6Hz,1H),7.43(d,J＝5.2Hz,1H),7.16-7.14(m,1H); as shown in fig. 44 as shown in fig. 45: 13C NMR(100MHz,CDCl3 ) Delta 157.3,133.1,128.4,127.9,126.9,126.4.
4- (Furan-2-yl) -1,2,3-thiadiazole (3 w): yield 60%;22.4mg; brown liquid; as shown in fig. 46: 1H NMR(400MHz,CDCl3 ) Delta 8.59 (s, 1H), 7.56 (s, 1H), 7.16 (d, j=3.2 hz, 1H), 6.59-6.57 (m, 1H); as shown in fig. 47: 13C NMR(100MHz,CDCl3 ) Delta 154.7,146.6,143.4,128.4,111.9,109.5.
4- (Naphthalen-1-yl) -1,2,3-thiadiazole (3 x): 77% yield; 41mg; white solid; melting point is 202-204 ℃; ：1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.10-8.08(m,1H),7.99-7.94(m,2H),7.76-7.74(m,1H),7.60-7.51(m,3H); as shown in FIG. 48 and FIG. 49 ：13C NMR(100MHz,CDCl3)δ161.9,134.2,133.8,131.4,129.9,128.5,128.4,127.1,126.3,126.3,125.2,125.1.
(E) -4-styryl-1,2,3-thiadiazole (3 y): 65% yield; 30.6mg; white solid; the melting point is 81-83 ℃; ：1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.72(d,J＝15.2Hz,1H),7.58(d,J＝8.0Hz,2H),7.45(s,1H),7.41(t,J＝8.0Hz,2H),7.33(t,J＝8.0Hz,1H); as shown in fig. 50 is shown in fig. 51: 13CNMR(100MHz,CDCl3 ) Delta 161.2,136.1,134.6,130.2,128.8,128.7,126.9,117.1.
4- (4- (PHENYLETHYNYL) phenyl) -1,2,3-thiadiazole (4) in 70% yield; 46mg; white solid; melting point is 126-128 ℃; ：1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.06(d,J＝8.4Hz,2H),7.68(d,J＝8.4Hz,2H),7.58-7.55(m,2H),7.39-7.36(m,3H); as shown in FIG. 52, theoretical value [ M+H ] +: 263.0637 of HRMS of ：13C NMR(100MHz,CDCl3)δ161.2,132.3,131.6,130.4,130.3,128.5,128.4,127.3,124.4,122.9,91.0,88.8.C16H10N2S as shown in FIG. 53, measured value: 263.0634.
4- ([ 1,1' -Biphenyl ] -4-yl) -1,2,3-thiadiazole (5) in 83% yield; 49.4mg; white solid at 183-184 ℃; ：1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.14-8.12(m,2H),7.76-7.74(m,2H),7.68-7.67(m,2H),7.50-7.46(m,2H),7.41-7.38(m,1H); as shown in fig. 54 as shown in fig. 55: 13CNMR(100MHz,CDCl3 ) Delta 162.5,142.2,140.2,129.8,129.7,128.9,127.8,127.8,127.4,127.0.
The foregoing is merely illustrative of specific embodiments of the present invention, and the scope of the invention is not limited thereto, but any modifications, equivalents, improvements and alternatives falling within the spirit and principles of the present invention will be apparent to those skilled in the art within the scope of the present invention.

Claims (1)

1. The synthesis method of the 1,2, 3-thiadiazole derivative is characterized by comprising the following steps of: taking N-p-toluenesulfonyl hydrazone acetophenone derivatives as raw materials, and carrying out [4+1] cyclization reaction with ammonium thiocyanate under a metal-free condition to generate 1,2, 3-thiadiazole derivatives; the reaction general formula of the synthesis method of the 1,2, 3-thiadiazole derivative is as follows:
；
The substituent R is hydrogen or R is halogen F, halogen Cl, halogen Br, halogen I or one or more than two of alkyl, alkoxy, phenyl, nitro, fluoroalkyl and fluoroalkoxy; the number of the substituents is 1-2;
the synthesis method of the 1,2, 3-thiadiazole derivative comprises the following steps:
step one, under the metal-free condition, mixing N-p-toluenesulfonyl hydrazone acetophenone or N-p-toluenesulfonyl hydrazone acetophenone derivatives with ammonium thiocyanate to obtain a mixture;
Step two, adding additives, an oxidant and a solvent into the mixture;
setting reaction temperature and reaction time, and performing reaction;
Step four, separating a product after the reaction is finished to obtain a1, 2, 3-thiadiazole derivative;
the molar ratio of the N-p-toluenesulfonyl hydrazone acetophenone or the N-p-toluenesulfonyl hydrazone acetophenone derivative to the ammonium thiocyanate is 1:1-1:3;
The additive is one of potassium iodide, ammonium iodide, cuprous iodide, tetrabutylammonium iodide, diacetyl iodobenzene and iodine;
The oxidant is one of potassium persulfate, ammonium persulfate and tert-butyl hydroperoxide;
the solvent is one of absolute ethyl alcohol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and acetonitrile;
the reaction time is 1-12 hours;
The reaction temperature is from room temperature to 100 ℃.
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Title
Jiangfei Chen et al..TBAI-Catalyzed Reaction between N-Tosylhydrazones and Sulfur: A Procedure toward 1,2,3-Thiadiazole.J. Org. Chem..2015,第81卷(第1期),271-275. *
Weiwei Li et al..Synthesis of 4-Aryl-1,2,3-Thiadiazoles via NH4I-Catalyzed Cyclization of N-Tosylhydrazones with Sulfur.ChemistrySelect.2019,第4卷(第35期),10587-10590. *
Yuhan Lu et al..Diiiodine/Potassium Persulfate Mediated Synthesis of 1,2,3-Thiadiazoles from N-Tosylhydrazones and a Thiocyanate Salt as a Sulfur Source under Transition-Metal-Free Conditions.Synlett.2021,第32卷(第10期),1044-1048. *

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